Concept Of Blood-brain Barrier Research Articles

Circumventing the blood–brain barrier

If the brain is the body’s central processing unit, then the blood–brain barrier is its firewall. A specialized network of cells that lines the brain’s vascular system, the blood–brain barrier selectively ushers in nutrients and other essential biomolecules while denying entry to most everything else. But the same system that protects the brain also stymies many therapeutics that could potentially treat disease. Fig. 1. In November 2015, researchers at Sunnybrook Health Sciences Centre in Toronto began a clinical trial to noninvasively breach the blood–brain barrier with focused ultrasound in an attempt to deliver chemotherapy to brain tumors. Image courtesy of Doug Nicholson (Sunnybrook, Toronto). A handful of drugs slip into the brain by passive diffusion—among them, antidepressants and medications for schizophrenia and epilepsy, along with caffeine, alcohol, and nicotine. These molecules are exceedingly small. They also can readily dissolve into the lipid membranes that encase blood–brain barrier cells. But new drug leads of this type are growing more elusive. “Most of the small molecule combinations have been explored,” says biomedical engineer Peter Searson at Johns Hopkins University in Baltimore, MD. Given these challenges, researchers are looking for other ways to slip past the barrier. Brain-penetrating antibodies and viruses could, for example, ferry therapeutic cargo across the border. A few groups are using ultrasound to temporarily open parts of the blood–brain barrier. “Over the last 20 years, blood–brain barrier research went from just a little small cottage industry to people really bringing the newest tools and approaches to bear on problem,” says bioengineer Eric Shusta at the University of Wisconsin–Madison. Finding ways to stealthily shuttle drugs across the blood–brain barrier could have big therapeutic implications. Although attempts to penetrate the barrier have only recently gained steam, the blood–brain barrier concept has been around for more than 100 years. The origins of the idea …

Mechanism of West Nile virus neuroinvasion: a critical appraisal.

West Nile virus (WNV) is an important emerging neurotropic virus, responsible for increasingly severe encephalitis outbreaks in humans and horses worldwide. However, the mechanism by which the virus gains entry to the brain (neuroinvasion) remains poorly understood. Hypotheses of hematogenous and transneural entry have been proposed for WNV neuroinvasion, which revolve mainly around the concepts of blood-brain barrier (BBB) disruption and retrograde axonal transport, respectively. However, an over‑representation of in vitro studies without adequate in vivo validation continues to obscure our understanding of the mechanism(s). Furthermore, WNV infection in the current rodent models does not generate a similar viremia and character of CNS infection, as seen in the common target hosts, humans and horses. These differences ultimately question the applicability of rodent models for pathogenesis investigations. Finally, the role of several barriers against CNS insults, such as the blood-cerebrospinal fluid (CSF), the CSF-brain and the blood-spinal cord barriers, remain largely unexplored, highlighting the infancy of this field. In this review, a systematic and critical appraisal of the current evidence relevant to the possible mechanism(s) of WNV neuroinvasion is conducted.

26IN - Brain Metastasis: Challenges in Understanding Pathogenesis and in Designing Clinical Trials

ABSTRACT The presence of brain metastases (BM) remains a therapeutic challenge as most trials with the exception of local treatment with surgery and radiosurgery in patients with solitary BM have failed. The negative trials suggest that the disease in the brain is not the principal determinant of life expectancy in patients with disseminated disease. Large trials without enrichment of the study population by a predictive biomarker are also unlikely to be successful. The blanket use of whole brain radiotherapy for multiple BMs is also no longer tenable. The concept of blood brain barrier, unlikely to be of significance in patients with enhancing brain metastases, should not be a bar to the use of chemotherapy, where the principal determinant of efficacy is likely to be chemoresponsiveness of systemic disease. Successful use of prophylactic brain treatment is predicated on the assumption that brain dissemination is a late metastatic event. Metastases suppressors, with mode of action spanning the metastatic cascade, have prophylactic efficacy in vivo, although the studies are mostly based on non-spontaneous models, which are unlikely to reflect the true clinical situation. Nevertheless some agents are approaching the time of clinical application. The successful development of new therapies for BMs needs refinement of the current trial design. Phase I/II studies of new agents should not exclude patients with BM to provide “proof of principle” of therapeutic efficacy in the brain. Subsequent trials, with survival as the primary endpoint, should focus on patient population where BM are likely to be the determinants of outcome (i.e. with inactive systemic disease) and enriched for a predictive biomarker. Large trials, even in a single tumour type, testing a single agent or a combination, either alone or in addition to standard treatment without appropriate patient selection are likely to continue to fail. Disclosure The author has declared no conflicts of interest.

Transvascular fluid exchange disturbed by capillary injuries

Fluid exchange disorders due to capillary lesions are numerous and their extent depends on the underlying disease as well as the capillary structure of the affected organ. The inflammatory cascade, triggered by sepsis or reperfusion injury, is mediated by several humoral mediators and activated blood cells. These include pro-inflammatory cytokines, arachidonic acid, proteases, oxygen free radicals, polymorphonuclears, procoagulant, complement and fibrinolytic system. The interaction between these mediators leads to a loss of endothelial integrity, a loss of basment membrane and a disruption of the interstitial matrix, with wasting of the endothelial cytoskeleton. The alteration in permeability induces transcapillary exudation of water and protein in the interstitial space, leading to organ dysfunction, mainly the lungs and splanchnic organs. Nitric oxyde, by modulating the response of the endothelium to the cellular interaction may protect against capillary injury. Capillary "stress lesions" following microvascular hypertension are the physiological basis of neurogenic or high altitude pulmonary oedema, and overinflation injury from mechanical ventilation. The anatomic specific features of the cerebral capillaries resulted in the well known concept of blood brain barrier with it's changeing morphology. Under the effect of humoral mediators and cellular interactions, the endothelial cells are able, via a calcium-mediated mechanism, to contract and to modify capillary permeability, leading to vasogenic oedema.

The blood-brain barrier in hypoxia.

The concept of blood-brain barrier has moved over the past years from a passive and relatively immutable structure to a more dynamic interface between blood and brain tissue. The transport mechanisms regulating this adaptative interface might be considered as the most sensitive elements to change such as hypoxia. Among various carrier mediated transports existing at the blood-brain barrier, glucose transport seems to play a predominant role. In severe hypoxia, progressive changes in glucose transport are occurring. These modifications associated with hypoxia can lead to deleterious events when reaching critical threshold. In addition the appearance of vasogenic edema due to changes in cerebral-blood flow, can possibly be prevented by some pharmacological interaction such as the use of selective brain calcium channel blockers.